Immune-related adverse events of immune checkpoint inhibitors and the impact of sex—what we know and what we need to learn

We read with interest the article by Khoja et al. [1.Khoja L. Day D. Wei-Wu Chen T. et al.Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review.Ann Oncol. 2017; 28: 2377-2385Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar], in which the authors reviewed systematically tumor- and class-specific patterns of immune-related adverse events of immune-checkpoint inhibitors. Their analysis revealed distinct immune related adverse events (irAE) profiles for anti-CTLA4 and anti-PD1/PDL1 antibodies, as well as different tumor histologies. The authors correctly point out various factors which could contribute to these distinct irAE profiles in different tumor types, such as differences in the immune cell infiltration and neoantigen formation, and suggest that differences in patient characteristics, such as pharmacologic responses, microbiome and comorbidities may as well play a role in this context. However, they do not mention a further important determinant of immune responses: a patient's sex. Sex is a biological variable that affects immune responses to both self and foreign antigens across various species [2.Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (2373) Google Scholar]. Different mechanisms could contribute to the overall stronger immune responses found in women as compared with men, including the localization of immune related genes and miRNA implicated in their regulation on the X chromosome and the control of immune cell differentiation and function by sex hormones [2.Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (2373) Google Scholar]. The incidence of autoimmune diseases is significantly higher in women, and alterations of sex hormone levels in pregnancy or menopause are known to affect their outcome [2.Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (2373) Google Scholar]. Thus, types, frequency and/or severity of irAEs may—in addition to the factors discussed by Khoja et al. —as well be influenced by sex. While the sexual dimorphism in drug response, with differences in metabolism due to variances in body size, distribution volumes, sex hormone levels and activity of enzymes is well known in cardiovascular medicine [3.Garcia M. Mulvagh S.L. Merz C.N.B. et al.Cardiovascular disease in women: clinical perspectives.Circ Res. 2016; 118: 1273-1293Crossref PubMed Scopus (519) Google Scholar], its potential clinical relevance in oncology is largely unknown and ignored. Generally, in oncology, the balance between the efficacy and toxicity of a drug might not be the same in men and in women. To understand this balance is a major challenge for drug development. Especially for checkpoint inhibitors, and in view of a positive correlation between the occurrence of irAEs and response rates, the question whether sex differences are present is of particular importance [4.Michot J.M. Bigenwald C. Champiat S. et al.Immune-related adverse events with immune checkpoint blockade: a comprehensive review.Eur J Cancer. 2016; 54: 139-148Abstract Full Text Full Text PDF PubMed Scopus (1366) Google Scholar]. There is emerging evidence from animal experiments showing that PD-1 expression is sex-dependent and modulated by estrogens. Moreover, data from preclinical melanoma models and clinical trials suggests that female sex is a predictor of poor response to anti-PD-1 therapy [5.Nosrati A. Tsai K.K. Goldinger S.M. et al.Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.Br J Cancer. 2017; 116: 1141-1147Crossref PubMed Scopus (94) Google Scholar]. To the best of our knowledge, data on the impact of sex on tumor response, as well as a possible correlation with irAEs for different types of checkpoint inhibitors and tumor types have not been reported and are urgently required. Inadequate inclusion of women in clinical trials in many disciplines, including oncology, despite the recommendations of important regulatory bodies such as the Food and Drug Administration and the National Institute of Health [6.Geller S.E. Koch A. Pellettieri B. et al.Inclusion, analysis, and reporting of sex and race/ethnicity in clinical trials: have we made progress?.J Womens Health (Larchmt). 2011; 20: 315-320Crossref PubMed Scopus (214) Google Scholar] is only one reason why obtaining this kind of data is challenging. In our view, sex is a fundamental biological variable, affecting a vast range of cellular functions in different organs, with impact in both physiological and pathological conditions, which deserves more attention in oncology. None declared.